Systems and methods for ionization

ABSTRACT

A system for analyzing a sample includes a chromatographic device, an electrospray source, and a mass resolving device. The chromatographic device is configured to separate components of the sample as a function of retention time within a chromatographic column. The electrospray source is configured to direct a first portion of a flow from the chromatographic device via a waste outlet to a pressurized waste reservoir, direct a second portion of the flow to an electrospray ionization outlet to form a spray, and charge and desolvate the spray to form ions of the components of the sample. A flow rate of the second portion of the liquid flow is substantially determined by a pressure of the pressurized waste reservoir. The mass resolving device configured to receive the ions and characterize the mass-to-charge ratio of the ions.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional under 35 U.S.C. § 121 and claims thepriority benefit of co-pending U.S. patent application Ser. No.14/935,782, filed Nov. 9, 2015. The disclosure of the foregoingapplication is incorporated herein by reference.

FIELD

The present disclosure generally relates to the field of massspectrometry including systems and methods for ionization.

INTRODUCTION

Liquid Chromatography Mass Spectrometry (LC-MS) combines liquidchromatography (LC), such as High Performance Liquid Chromatography(HPLC) and Ultrahigh Performance Liquid Chromatography (UHPLC), forseparation of analytes in a sample with Mass Spectrometry (MS) todetect, quantify, and identify the analytes. Generally, the effluentfrom the HPLC or UHPLC is directed into the source of the massspectrometer where the analytes are ionized and the ions analyzed todetermine the mass of the analytes and fragments thereof. However, atanalytical LC flow rates (typically about 100 microliter per minute(μL/min) to about 1000 μL/min or more), there can be significant signalvariability, especially at low concentrations of analytes. Ionizationtechniques, such as electrospray ionization, can form charged dropletswhich are then desolvated in a gas flow. At analytical flow rates, therequired gas flow to desolvate the droplets can be significant(typically about 5 L/min to about 10 L/min or more). Turbulence in thegas flow or disruptions in the droplet formation are some of thepotential sources for the signal variability, particularly whenmonitoring specific ions for periods of time less than 20 milliseconds.

From the foregoing it will be appreciated that a need exists forimproved ion sources.

SUMMARY

In a first aspect, a system for analyzing a sample can include anelectrospray source and a mass resolving device. The electrospray sourcecan be configured to direct a first portion of a flow from achromatographic device via a waste outlet to a pressurized wastereservoir, direct a second portion of the flow to an electrosprayionization outlet to form a spray, and charge and desolvate the spray toform ions of the components of the sample. A flow rate of the secondportion of the liquid flow can be substantially determined by a pressureof the pressurized waste reservoir. The mass resolving device can beconfigured to receive the ions, and characterize the mass-to-chargeratio of the ions.

In various embodiments of the first aspect, the system can include achromatographic device configured to separate components of the sampleas a function of retention time within a chromatographic column.

In various embodiments of the first aspect, the electrospray ionizationoutlet can include at least one electrospray emitter. In particularembodiments, the electrospray emitter includes a platinum wire toprovide a high voltage to the second portion of the flow at theelectrospray emitter.

In particular embodiments, the at least one electrospray emitter caninclude an array of electrospray emitters. In particular embodiments,the array of electrospray emitters can include at least about 5electrospray emitters. In particular embodiments, the array ofelectrospray emitters includes not greater than about 1000 emitters. Inparticular embodiments, the array of electrospray emitters includes notgreater than about 500 emitters.

In particular embodiments, an electric field strength at the at leastone electrospray emitter is between about 2×10⁷ V/m and about 2×10¹°V/m.

In various embodiments of the first aspect, the electrospray ionizationoutlet can include a counter electrode.

In various embodiments of the first aspect, the electrospray source canbe configured to provide a nebulization gas at the electrosprayionization outlet. In particular embodiments, the nebulization gas canhave a pressure of between about 1 psi and about 5 psi.

In various embodiments of the first aspect, a split ratio of the secondflow to the first flow can be between about 1:1 to about 1:2000. Inparticular embodiments, the split ratio can be between about 1:50 toabout 1:1000.

In various embodiments of the first aspect, the flow rate of the secondportion can be between about 10 nanoliter per minute (nL/min) to about25 μL/min per emitter nozzle.

In various embodiments of the first aspect, the pressure of thepressurized waste container can be between about 2 psi and about 50 psi.

In a second aspect, an electrospray source can include an inlet forreceiving a liquid flow from a liquid chromatography column, a wasteoutlet for directing a first portion of the liquid flow to a pressurizedwaste reservoir, and an electrospray ionization outlet. The electrosprayionization outlet can be configured to generate ions from a secondportion of the liquid flow. A flow rate of the second portion of theliquid flow can be substantially determined by a pressure of thepressurized waste reservoir.

In various embodiments of the second aspect, the electrospray ionizationoutlet can include at least one electrospray emitter. In particularembodiments, the electrospray emitter can include a platinum wire toprovide a high voltage to the second portion of the flow at theelectrospray emitter.

In particular embodiments, the at least one electrospray emitter caninclude an array of electrospray emitters. In particular embodiments,the array of electrospray emitters can include at least about 5electrospray emitters. In particular embodiments, the array ofelectrospray emitters can include not greater than about 1000 emitters.In particular embodiments, the array of electrospray emitters caninclude not greater than about 500 emitters.

In particular embodiments, an electric field strength at the at leastone electrospray emitter can be between about 2×10⁷ V/m and about 2×10¹°V/m.

In various embodiments of the second aspect, the electrospray ionizationoutlet can include a counter electrode.

In various embodiments of the second aspect, the electrospray source canbe configured to provide a nebulization gas at the electrosprayionization outlet.

In particular embodiments, the nebulization gas can have a pressure ofbetween about 1 psi and about 5 psi.

In various embodiments of the second aspect, a split ratio of the secondflow to the first flow can be between about 1:1 to about 1:2000. Inparticular embodiments, the split ratio can be between about 1:50 toabout 1:1000.

In various embodiments of the second aspect, the flow rate of the secondportion can be between about 10 nL/min to about 25 μL/min per emitternozzle.

In various embodiments of the second aspect, the pressure of thepressurized waste container can be between about 2 psi and about 50 psi.

In a third aspect, a method for analyzing a liquid sample can includesupplying a flow of a liquid sample to an inlet of a electrospraysource, splitting the flow into a first portion directed to apressurized waste container and a second portion to a electrosprayionization outlet, adjusting a pressure within the pressurized wastecontainer to control a flow rate of the second portion to theelectrospray ionization outlet, generating ions of components of theliquid sample at the electrospray ionization outlet, and analyzing theions using a mass spectrometer to identify the components of the sample.

In various embodiments of the third aspect, the method can furtherinclude providing a high voltage to the second portion of the flow atthe electrospray emitter.

In various embodiments of the third aspect, the electrospray ionizationoutlet can include at least one electrospray emitter. In particularembodiments, the electrospray emitter can include a platinum wire.

In particular embodiments, the at least one electrospray emitter caninclude an array of electrospray emitters. In particular embodiments,the array of electrospray emitters can include at least about 5electrospray emitters. In particular embodiments, the array ofelectrospray emitters can include not greater than about 1000 emitters.In particular embodiments, the array of electrospray emitters caninclude not greater than about 500 emitters.

In particular embodiments, the method can further include generating anelectric field having an electric field strength at the at least oneelectrospray emitter of between about 2×10⁷ V/m and about 2×10¹° V/m.

In various embodiments of the third aspect, the electrospray ionizationoutlet can include a counter electrode.

In various embodiments of the third aspect, the method can furtherinclude providing a nebulization gas at the electrospray ionizationoutlet. In particular embodiments, the nebulization gas can be providedat a pressure of between about 1 psi and about 5 psi.

In various embodiments of the third aspect, a split ratio of the secondflow to the first flow can be between about 1:1 to about 1:2000. Inparticular embodiments, the split ratio can be between about 1:50 toabout 1:1000.

In various embodiments of the third aspect, the flow rate of the secondportion can be between about 10 nL/min to about 25 μL/min.

In various embodiments of the third aspect, the pressure within thepressurized waste container can be between about 2 psi and about 50 psi.

DRAWINGS

For a more complete understanding of the principles disclosed herein,and the advantages thereof, reference is now made to the followingdescriptions taken in conjunction with the accompanying drawings, inwhich:

FIG. 1 is a block diagram of an exemplary mass spectrometry system, inaccordance with various embodiments.

FIGS. 2A and 2B are diagrams illustrating an exemplary electrospraysource, in accordance with various embodiments. FIG. 2A is a crosssection view and FIG. 2B is a perspective view.

FIG. 3 is a flow diagram of an exemplary method for generating ions formass analysis, in accordance with various embodiments.

FIG. 4 is a graph showing the flow to the ionization outlet issubstantially independent of inlet flow at a fixed back pressure, inaccordance with various embodiments.

FIG. 5 is a graph showing the flow to the ionization outlet is dependenton back pressure, in accordance with various embodiments.

FIG. 6 is a graph showing the uniformity of the ion intensity comparedto a traditional high flow source, in accordance with variousembodiments.

FIGS. 7A and 7B are diagrams illustrating an exemplary electrosprayemitter array, in accordance with various embodiments. FIG. 7A is across section view and FIG. 7B is a perspective view.

It is to be understood that the figures are not necessarily drawn toscale, nor are the objects in the figures necessarily drawn to scale inrelationship to one another. The figures are depictions that areintended to bring clarity and understanding to various embodiments ofapparatuses, systems, and methods disclosed herein. Wherever possible,the same reference numbers will be used throughout the drawings to referto the same or like parts. Moreover, it should be appreciated that thedrawings are not intended to limit the scope of the present teachings inany way.

DESCRIPTION OF VARIOUS EMBODIMENTS

Embodiments of systems and methods for ionization are described herein.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the described subject matter inany way.

In this detailed description of the various embodiments, for purposes ofexplanation, numerous specific details are set forth to provide athorough understanding of the embodiments disclosed. One skilled in theart will appreciate, however, that these various embodiments may bepracticed with or without these specific details. In other instances,structures and devices are shown in block diagram form. Furthermore, oneskilled in the art can readily appreciate that the specific sequences inwhich methods are presented and performed are illustrative and it iscontemplated that the sequences can be varied and still remain withinthe spirit and scope of the various embodiments disclosed herein.

All literature and similar materials cited in this application,including but not limited to, patents, patent applications, articles,books, treatises, and internet web pages are expressly incorporated byreference in their entirety for any purpose. Unless described otherwise,all technical and scientific terms used herein have a meaning as iscommonly understood by one of ordinary skill in the art to which thevarious embodiments described herein belongs.

It will be appreciated that there is an implied “about” prior to thetemperatures, concentrations, times, pressures, flow rates,cross-sectional areas, etc. discussed in the present teachings, suchthat slight and insubstantial deviations are within the scope of thepresent teachings. In this application, the use of the singular includesthe plural unless specifically stated otherwise. Also, the use of“comprise”, “comprises”, “comprising”, “contain”, “contains”,“containing”, “include”, “includes”, and “including” are not intended tobe limiting. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the present teachings.

As used herein, “a” or “an” also may refer to “at least one” or “one ormore.” Also, the use of “or” is inclusive, such that the phrase “A or B”is true when “A” is true, “B” is true, or both “A” and “B” are true.Further, unless otherwise required by context, singular terms shallinclude pluralities and plural terms shall include the singular.

A “system” sets forth a set of components, real or abstract, comprisinga whole where each component interacts with or is related to at leastone other component within the whole.

Mass Spectrometry Platforms

Various embodiments of mass spectrometry platform 100 can includecomponents as displayed in the block diagram of FIG. 1. In variousembodiments, elements of FIG. 1 can be incorporated into massspectrometry platform 100. According to various embodiments, massspectrometer 100 can include an ion source 102, a mass analyzer 104, anion detector 106, and a controller 108.

In various embodiments, the ion source 102 generates a plurality of ionsfrom a sample. The ion source can include, but is not limited to, amatrix assisted laser desorption/ionization (MALDI) source, electrosprayionization (ESI) source, atmospheric pressure chemical ionization (APCI)source, atmospheric pressure photoionization source (APPI), inductivelycoupled plasma (ICP) source, electron ionization source, chemicalionization source, photoionization source, glow discharge ionizationsource, thermospray ionization source, and the like.

In various embodiments, the mass analyzer 104 can separate andcharacterize ions based on a mass-to-charge ratio of the ions. Theseions can carry one or more charges. For example, the mass analyzer 104can include a quadrupole mass filter analyzer, a quadrupole ion trapanalyzer, a time-of-flight (TOF) analyzer, an electrostatic trap (e.g.,Orbitrap) mass analyzer, Fourier transform ion cyclotron resonance(FT-ICR) mass analyzer, and the like. In various embodiments, the massanalyzer 104 can also be configured to fragment the ions using collisioninduced dissociation (CID) electron transfer dissociation (ETD),electron capture dissociation (ECD), photo induced dissociation (PID),surface induced dissociation (SID), and the like, and further separatethe fragmented ions based on the mass-to-charge ratio.

In various embodiments, the ion detector 106 can detect ions. Forexample, the ion detector 106 can include an electron multiplier, aFaraday cup, and the like. Ions leaving the mass analyzer can bedetected by the ion detector. In various embodiments, the ion detectorcan be quantitative, such that an accurate count of the ions can bedetermined.

In various embodiments, the controller 108 can communicate with the ionsource 102, the mass analyzer 104, and the ion detector 106. Forexample, the controller 108 can configure the ion source orenable/disable the ion source. Additionally, the controller 108 canconfigure the mass analyzer 104 to select a particular mass range todetect. Further, the controller 108 can adjust the sensitivity of theion detector 106, such as by adjusting the gain. Additionally, thecontroller 108 can adjust the polarity of the ion detector 106 based onthe polarity of the ions being detected. For example, the ion detector106 can be configured to detect positive ions or be configured todetected negative ions.

In various embodiments, the system can be coupled with a chromatographydevice 110. The chromatography device 110 can include a gaschromatograph (GC), a liquid chromatograph (LC), such as an HPLC or aUHPLC, or the like. The chromatography device can separate components ofa sample according to the retention times of the individual componentswithin the column. In various embodiments, the chromatography column caninclude a material that interacts with at least some of the componentsof the sample. The interactions between the components and the columnmaterial can retard the flow of the components through the column,resulting in a retention time that is a function of the extent of theinteraction between the component and the column material. Theinteractions can be based on a size of the component, a hydrophobicityof the component, the charge of the component, an affinity of the columnmaterial for the component, or the like. As such, the column can atleast partially separate components of the sample from one another.

Ion Source

FIGS. 2A and 2B illustrate of an exemplary electrospray source 200. FIG.2A is a cross-section view and FIG. 2B is a perspective view. Theelectrospray source 200 can include a LC effluent inlet 202, a wasteoutlet 204, and an electrospray outlet 206 connected at a T-junction 208housed within a body 210. In various embodiments, the T-junction 208 canbe formed of or lined with fused silica.

In various embodiments, effluent from an LC column can be directed tothe LC effluent inlet 202, where, from the T junction 208, a firstportion can be directed to the waste outlet 204 and to a pressurizedwaste container and a second portion can be directed to the ionizationoutlet 206 where ions for MS analysis can be formed. The amount ofeffluent sent to the ionization outlet 206 can be a function of thepressure in the pressurized waste container. In various embodiments, thewaste container can be pressurized to between about 2 psi and about 50psi, although other pressures are possible. In various embodiments, theresulting second portion of the effluent flow that is sent to theionization outlet can be between about 10 nL/min to about 25 μL/min peremitter. In various embodiments with multiple emitters, the total flowrate of the second portion can be, for example, up to about 12.5 mL/minfor an array of 500 emitters.

In various embodiments, the resultant ratio between the second portion(to the ionization outlet) and the first portion (to the wastecontainer) can be between about 1:50 to about 1:2000, such as betweenabout 1:100 to about 1:1000. In certain embodiments with multipleelectrospray emitters, a much higher fraction or even the entireeffluent flow can be directed to the ionization outlets.

The LC effluent inlet 202 can include an inlet ferrule 212 having a LCeffluent tubing channel 214 formed there through. Additionally, the LCeffluent inlet 202 can include a ferrule nut 216. In variousembodiments, LC effluent tubing 242 can be positioned within the LCeffluent tubing channel 214 of the inlet ferrule 212 and the ferrule nut216 can couple the inlet ferrule 212 to the body 210 to form a liquidtight union between effluent tubing and the T-junction 208.

The waste outlet 204 can include a waste ferrule 218 having a wastetubing channel 220 formed there through. Additionally, the waste inlet204 can include a ferrule nut 222. In various embodiments, waste tubing244, coupled to the pressurized waste container, can be positionedwithin the waste tubing channel 220 of the waste ferrule 218 and theferrule nut 222 can couple the waste ferrule 218 to the body 210 to forma liquid tight union between the waste tubing and the T-junction 208.

The ionization outlet 206 can include an ionization ferrule 224 having achannel 226 formed there through. In various embodiments, a fused silicatubing 228 can be inserted through the channel 226. Alternatively, thechannel 226 can be lined with fused silica or other inert material. Invarious embodiments, the ionization outlet 206 can include one or moreelectrospray emitters 230 and a counter electrode 232. In variousembodiments, a portion of the effluent can be directed from theT-junction 208 down the channel 226 to the electrospray emitter 230. Invarious embodiments, a voltage can be applied the counter electrode 232to drive droplets and ions away from the electrospray emitters 230 as orafter they are formed.

In various embodiments, the electrospray emitter 230 can include asingle emitter. Alternatively, the electrospray emitters 230 can includebe arranged as an array of electrospray emitters 230, such as by anelectrospray chip. In particular embodiments, the multi-channel arraycan include at least about 5 electrospray emitters and generally notmore than about 1000 electrospray emitters, such as not more than about500 electrospray emitters. In various embodiments, at the electrosprayemitter 230, a Taylor cone can be formed by applying a high voltage. TheTaylor cone can generate a fine spray of charged droplets of theeffluent, which, after evaporation, can generate gas phase ions of thecomponents of the sample for mass spectrometry analysis.

In various embodiments, the high voltage can be applied by a highvoltage connection 234 and a metal wire 246, such as a platinum wire,inserted into the T-junction 208 where comes into contact with theliquid flowing along channel 226 to the electrospray emitter 230. Inalternate embodiments, the high voltage can be applied to theelectrospray emitter 230, such as when using an electrospray chip withmultiple electrospray emitters 230, in other ways without passingthrough the T-junction 208. Alternatively, the body 210 could beconstructed from metal, which would eliminate the need for a fourth port234. In various embodiments, the electric field at the electrosprayemitter 230 can preferentially be between about 2×10⁷ V/m and about2×10¹⁰ V/m. The electric field can be produced by the voltages appliedto the counter electrode and the emitter, and the strength can be afunction of the difference between the voltage applied to the counterelectrode and the voltage applied to the emitter.

In various embodiments, a sheath or nebulization gas can be supplied tothe electrospray emitter 230 to enhance the electrospray at higher flowrates and improve desolvation of the droplets. The gas can be suppliedthrough gas inlet 236 and directed around to the electrospray emitter230 and within a tube 248 circumscribing the electrospray emitter 230 bythe electrospray ionization ferrule 224. O-rings 238 and 240 can beutilized to create a gas tight seal within the ionization outlet 206. Invarious embodiments, the nebulization gas, when supplied, can have apressure of between about 0.1 psi and about 15 psi, such as betweenabout 1.0 psi and about 5.0 psi. As is understood in the art, drying andcounter current gases can be supplied to enhance desolvation of thedroplets.

FIGS. 7A and 7B illustrate of an exemplary emitter array 700. FIG. 7A isa cross-section view and FIG. 7B is a perspective view. Emitter array700 can include a plurality of emitters 702 having an emitter channel704 formed therein. The emitter channel 704 can connect to effluentdistribution channel 706 that can distribute the second portion of theeffluent to the emitters 702 of the emitter array 700. In variousembodiments, emitter channel 704 can be formed as a slit across theemitters 702 of the array, such that a single channel is formed.Alternatively, each emitter 702 can have a separated emitter channel 704connected to the effluent distribution channel 706 and not in fluidiccommunication with the adjacent emitter channels 704 except through theeffluent distribution channel 706.

Additionally, emitter array 700 can include a sheath gas channel 708 forthe distribution of a sheath gas flow adjacent to the emitters 702. Invarious embodiments, the surface 710 on the emitter array 700 can act asa counter electrode by applying a different high voltage potential tothe surface 710 and the emitters 702, provided the surface 710 and theemitters 702 are electrically isolated, such as with a dielectricmaterial, other material, or a physical gap. In various embodiments, theemitter array 700 can be formed with a top layer 720 formed of aconductive material and a bottom layer 730 formed of a conductivematerial with a layer of dielectric material 740 between the top andbottom layers so as to provide electrical isolation of the surface 710from the emitters 702. In other embodiments, the emitter array 700 canbe formed of a non-conductive or dielectric material and the surface 710and the emitters 702 can be coated with a conductive layer.

FIG. 3 is a flow diagram illustrating an exemplary method 300 ofanalyzing a sample using a LC-MS system with an electrospray source,such as electrospray source 200 of FIG. 2.

At 302, a sample flow, such as an effluent from an LC system can besupplied to an inlet of an electrospray source, such as LC inlet 202 ofFIG. 2. In various embodiments, the sample flow can include a pluralityof components of a sample that have been separated as a function of timeby the LC system, such that a small number of components reach the inletat a given time.

At 304, the electrospray source can split the flow between a firstportion to a waste outlet and a second portion to an ionization outlet.In various embodiments, the ratio between the second portion and thefirst portion can be between about 1:1 to about 1:2000, such as about1:50 to about 1:1000. In various embodiments, the resultant secondportion can provide between about 1 μL/min to about 25 μL/min peremitter to the ionization outlet. In various embodiments with multipleemitters, the second portion can provide a total flow rate, for example,of between about 500 μL/min to about 12.5 mL/min for an emitter arraywith 500 emitters.

At 306, the backpressure in the waste outlet can be adjusted to regulatethe flow to the ionization outlet. The waste outlet can be directed to apressurized waste container and the pressure within the waste containercan be adjusted to achieve the desired flow to the ionization outlet. Invarious embodiments, the pressure within the waste contained can bebetween about 10 psi and about 50 psi.

At 308, the liquid flowing to the ionization outlet can be ionized, suchas by electrospray ionization. In various embodiments, one or moreelectrospray emitters can be arranged at the ionization outlet and ahigh voltage can be applied to generate an electric field having anelectric field strength at the electrospray emitter of between about2×10⁷ V/m and about 2×10¹° V/m. The electrospray emitters can include asingle electrospray emitter with a metal wire, such as a platinum wire,an array of electrospray emitters, or other arrangements of electrosprayemitters. An array of electrospray emitters can include at least about 5electrospray emitters, such as not greater than about 1000 electrosprayemitters, even not greater than about 500 electrospray emitters.

At 310, a mass analyzer can analyze the ions to determine amass-to-charge ratio. As is known in the art, additional methods can beperformed on the ions, including MS/MS analysis where the ions arefragmented and the mass-to-charge ratios of the resulting ion fragmentsare determined.

While the present teachings are described in conjunction with variousembodiments, it is not intended that the present teachings be limited tosuch embodiments. On the contrary, the present teachings encompassvarious alternatives, modifications, and equivalents, as will beappreciated by those of skill in the art.

Further, in describing various embodiments, the specification may havepresented a method and/or process as a particular sequence of steps.However, to the extent that the method or process does not rely on theparticular order of steps set forth herein, the method or process shouldnot be limited to the particular sequence of steps described. As one ofordinary skill in the art would appreciate, other sequences of steps maybe possible. Therefore, the particular order of the steps set forth inthe specification should not be construed as limitations on the claims.In addition, the claims directed to the method and/or process should notbe limited to the performance of their steps in the order written, andone skilled in the art can readily appreciate that the sequences may bevaried and still remain within the spirit and scope of the variousembodiments.

Results

The flow to an example emitter is measured at various LC flows rangingfrom 100 μL/min to 700 μL/min with a waste reservoir pressure held fixedat 30 psi. FIG. 4 is a graph showing that the flow to the emitter issubstantially independent of the LC flow. As is shown, the flow to theemitter is maintained at about 1.6 μL/min over a range of LC flows ofbetween 100 μL/min and 700 μL/min. In this non-limiting example, thesplit ratio between the flow to the emitter and that to the wastereservoir ranges between 1:60 and 1:440.

The flow to the emitter is measured at various LC flows (100 μL/min, 400μL/min, and 600 μL/min) and various waste reservoir pressure rangingfrom 10 psi to 40 psi. FIG. 5 is a graph showing the linear dependenceof the emitter flow on the reservoir pressure. Additionally, therelationship between the emitter flow and the reservoir pressure issubstantially similar across the range of LC flows.

The stability of the source, as determined by variability in theintensity of ions measured by the ion detector, is compared between ahigh flow electro spray source and a split electrospray source asdescribed herein. A continuous flow of analyte at a fixed concentrationis supplied to the electrospray source and the mass spectrometer isconfigured to monitor a selected reaction (SRM mode). FIG. 6 shows thatthe high flow electrospray source exhibits significant variability overtime, whereas the variability from the split electrospray source issignificantly lower, showing the improved stability of the splitelectrospray source.

What is claimed is:
 1. A system for analyzing a sample comprising: anelectrospray source configured to direct a first portion of a flow froma chromatographic device via a waste outlet to a pressurized wastereservoir; direct a second portion of the flow to an electrosprayionization outlet to form a spray, a flow rate of the second portion ofthe liquid flow is substantially determined by a pressure of thepressurized waste reservoir, wherein the electrospray ionization outletincludes at least one electrospray emitter and the electrospray emitterincludes a platinum wire to provide a high voltage to the second portionof the flow at the electrospray emitter; and charge and desolvate thespray to form ions of the components of the sample; a mass resolvingdevice configured to: receive the ions; and characterize themass-to-charge ratio of the ions; and a controller configured to:adjusting the pressure within the pressurized waste container to controlthe flow rate of the second portion to the electrospray ionizationoutlet.
 2. The system of claim 1 further comprising a chromatographicdevice configured to separate components of the sample as a function ofretention time within a chromatographic column.
 3. The system of claim 1wherein the at least one electrospray emitter includes an array ofelectrospray emitters.
 4. The system of claim 3 wherein the array ofelectrospray emitters includes at least about 5 electrospray emitters.5. The system of claim 4 wherein the array of electrospray emittersincludes not greater than about 1000 emitters.
 6. The system of claim 1wherein an electric field strength at the at least one electrosprayemitter is between about 2×10⁷ V/m and about 2×10¹° V/m.
 7. The systemof claim 1 wherein the electrospray ionization outlet includes a counterelectrode.
 8. The system of claim 1 wherein the electrospray source isconfigured to provide a nebulization gas at the electrospray ionizationoutlet.
 9. The system of claim 8 wherein the nebulization gas has apressure of between about 1 psi and about 5 psi.
 10. The system of claim1 wherein a split ratio of the second flow to the first flow is betweenabout 1:1 to about 1:2000.
 11. The system of claim 1 wherein the flowrate of the second portion is between about 10 nL/min to about 25 μL/minper emitter nozzle.
 12. The system of claim 1 wherein the pressure ofthe pressurized waste container is between about 2 psi and about 50 psi.13. An electrospray source comprising: an inlet for receiving a liquidflow from a liquid chromatography column; a waste outlet for directing afirst portion of the liquid flow to a pressurized waste reservoir; andan electrospray ionization outlet configured to generate ions from asecond portion of the liquid flow, a flow rate of the second portion ofthe liquid flow is substantially determined by a pressure of thepressurized waste reservoir, wherein the electrospray ionization outletincludes at least one electrospray emitter and the electrospray emitterincludes a platinum wire to provide a high voltage to the second portionof the flow at the electrospray emitter.
 14. The electrospray source ofclaim 13 wherein the at least one electrospray emitter includes an arrayof electrospray emitters.
 15. The electrospray source of claim 14wherein the array of electrospray emitters includes at least about 5electrospray emitters.
 16. The electrospray source of claim 15 whereinthe array of electrospray emitters includes not greater than about 1000emitters.
 17. The electrospray source of claim 13 wherein an electricfield strength at the at least one electrospray emitter is between about2×10⁷ V/m and about 2×10¹⁰ V/m.
 18. The electrospray source of claim 13wherein the electrospray source is configured to provide a nebulizationgas at the electrospray ionization outlet.
 19. The electrospray sourceof claim 18 wherein the nebulization gas has a pressure of between about1 psi and about 5 psi.
 20. The electrospray source of claim 13 wherein asplit ratio of the second flow to the first flow is between about 1:1 toabout 1:2000.
 21. The electrospray source of claim 13 wherein the flowrate of the second portion is between about 10 nL/min to about 25 μL/minper emitter.
 22. The electrospray source of claim 13 wherein thepressure of the pressurized waste container is between about 2 psi andabout 50 psi.